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Science & Technology

September 22, 2008
Volume 86, Number 38
pp. 71-72

Science & Technology Concentrates

Catalytic Electrocyclization

Researchers have developed the first Lewis acid-catalyzed 6-π electrocyclization reaction, expanding the repertoire of synthetic techniques for efficiently cyclizing organic compounds (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200803336). In electrocyclizations, a single bond is formed between the ends of a system of conjugated double bonds, yielding a cyclic compound with one fewer double bond. Catalytic electrocyclizations have generally proven elusive, but Robert G. Bergman and Dirk Trauner of the University of California, Berkeley, and coworkers have now developed one for 6-π-electron starting materials (hexatriene systems). Previous groups had found that electron-withdrawing groups at the 2-position of hexatrienes made it easier to electrocyclize the compounds. The researchers therefore synthesized hexatrienes with an electron-withdrawing carbonyl group at the 2-position. After trying a variety of Lewis acids, they found that dimethylaluminum chloride enhanced the carbonyl group's electron-withdrawing effects and accelerated electrocyclization of the derivatized compounds by a substantial factor—55 in the case of the reaction shown. According to the researchers, the findings set the stage for milder electrocyclizations and could lead to asymmetric versions of such reactions.

Catching Catalyst Particles In Action

Analytical methods for probing catalytic nanocrystals while they mediate chemical reactions can uncover insights that lead to better catalysts. Designing those methods, however, remains a formidable challenge. Two teams of researchers have taken a step in that direction by demonstrating techniques for monitoring catalyzed oxidation and reduction reactions. In one case, Paul Mulvaney and coworkers of the University of Melbourne, in Australia, combined an analytical technique known as dark field microscopy with surface plasmon spectroscopy to directly measure the single-particle reaction rates of the fundamental steps of ascorbic acid oxidation by dissolved oxygen on gold nanoparticles (Nat. Nanotechnol., DOI:10.1038/nnano.2008.246). The particles hasten the reaction by serving as electron reservoirs that transfer charge from ascorbic acid to oxygen. In the other study, Andreas Stierle of the Max Planck Institute for Metal Research, in Stuttgart, Germany, and coworkers combined X-ray diffraction and transmission electron microscopy to probe oxidation-induced shape changes to the surfaces of rhodium nanoparticles supported on magnesium oxide (Science 2008, 321, 1654). They found that crystal morphology changes, which can be reversed by CO exposure, are driven by the formation of an oxygen-rhodium-oxygen surface oxide film that stabilizes the nanoparticles.

Structural Insights Into Shigella Virulence Factor

In 2006, the VirA virulence factor for the pathogenic bacterium Shigella flexneri was identified via biochemical assays as a protease that degrades microtubules in cells (Science 2006, 314, 985). Two independent groups now report X-ray crystal structures that suggest VirA neither functions as a protease nor degrades microtubules. Both the 2.4-?? structure by Benjamin W. Spiller and coworkers of Vanderbilt University Medical Center (Biochemistry, DOI: 10.1021/bi801533k) and the 3.0-?? structure by Alexander Wlodawer and coworkers of the National Cancer Institute's Macromolecular Crystallography Laboratory (Protein Sci., DOI: 10.1110/ps.037978.108) show that VirA is V-shaped with a prominent cleft between the N- and C-terminal domains. VirA had been thought to be similar to papain, a cysteine protease found in papaya, but the structures indicate that VirA lacks homology with papain or any other known protease. In biochemical assays by both teams, purified VirA alone is unable to cleave tubulin. Both teams suggest that VirA may act as a scaffold for an as-yet-undetected cellular factor, perhaps even a cysteine protease.

Angew. Chem. Int. Ed.
Blue chromophore includes a zinc-coordinated, four-residue cross-linking unit not seen before in a native protein structure.

An Unusual Blue Protein Chromophore

Ranasmurfin, a blue protein isolated from the nests of a type of Malaysian tree frog, has an unusual chromophore, as well as uncommon amino acid cross-links. An international team led by Alan Cooper of the University of Glasgow and James H. Naismith of the University of St. Andrews, both in Scotland, has solved a 1.16-?? crystal structure showing that ranasmurfin, a 26-kilodalton homodimer, is stabilized by unusual lysine tyrosyl quinone (LTQ) linkages (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200802901). This is the first time such modifications have been identified in a native protein. The crystal structure also reveals a four-residue bis(LTQ) linkage between the protein's subunits. The bis(LTQ) structure, together with two histidine residues, serves as the binding site for a Zn2+ ion and is a likely candidate for the protein's blue chromophore. The bridging atom in bis(LTQ) can't be unequivocally identified by just electron density, but the researchers suspect that it's nitrogen because a nitrogen moiety would make a good ligand for zinc, and similar N-linked compounds are often highly colored.

Colloidal Dumbbells Form Chiral Chains

© 2008 Nature
Macromolecular structures form in a magnetic field from silica nanoparticle (yellow or gray) dumbbells held together by iron oxide (green).

Silica nanoparticles joined together by iron oxide line up in a magnetic field to make chiral colloidal helices, reports a group led by Jérôme Bibette at the Paris-based Industrial Physics & Chemistry Higher Educational Institution (Nature 2008, 455, 380). The researchers used iron oxide to cement together pairs of 1-μm-diameter silica nanoparticles to make dumbbell shapes. When symmetric dumbbells were prepared from silica particles of similar size, they assembled in a magnetic field to form a chain in which the dumbbells aligned perpendicular to each other, with the iron oxide running down the center of the chain. When silica particles of different sizes were used to make asymmetric dumbbells, the aligned dumbbells formed a helical structure. Using the spheres as building blocks for macromolecules could provide a way to study steric interactions without confounding factors such as hydrogen bonding or electrostatic forces, the researchers say. The helices could also interact with circularly polarized light to rotate, potentially functioning as a motor to turn electromagnetic radiation into mechanical work.

Fullerene Traps Longest Metal Bond

Courtesy of Harry Dorn
C79N cage holds a bonded pair of yttrium atoms (green).

By trapping two terbium atoms within a C79N fullerene cage, chemists have created the longest metal-metal bond measured to date (J. Am. Chem. Soc., DOI: 10.1021/ja802417d). The terbium atoms share a single-electron bond a tad more than 3.9-?? long. A research team led by Alan L. Balch of the University of California, Davis, and Harry C. Dorn of Virginia Polytechnic Institute & State University prepared and characterized the endohedral fullerene, as well as an analog that holds a pair of yttrium atoms. To create the compounds, the researchers employed the Krätschmer-Huffman electric-arc process to vaporize graphite rods doped with either Tb4O7 or Y2O3. They then purified enough material for crystallographic and spectroscopic studies. Computational analyses of the yttrium analog indicate that the compound is a very stable radical in which the metal atoms share an unpaired electron in their bonding orbital. According to Dorn, these molecules represent a new class of metalloheterofullerenes. Such compounds could find practical applications as contrast agents for magnetic resonance imaging or could be used in new spintronic and semiconductor applications.

Chemistry For Beating Down Cocaine Abuse

Two new research papers reveal biochemical details that could improve the prospects for treating cocaine overdose and addiction. In one study, Chang-Guo Zhan of the University of Kentucky and colleagues used a computational approach involving transition-state simulations to design an enzyme that breaks cocaine into biologically inactive metabolites (J. Am. Chem. Soc. 2008, 130, 12148). The enzyme is a mutant version of the body's own butyrylcholinesterase enzyme, but as the researchers observed, it is 2,000 times more efficient at metabolizing cocaine. The new enzyme prevented convulsions and death in mice given a cocaine overdose. In another study, Pascal Romieu of France's National Institute for Health & Medical Research, in Strasbourg, and coworkers focused on curbing cocaine dependence (J. Neurosci. 2008, 28, 9342). Drug abuse is believed to alter regulation of gene expression in part through deacetylation of histones, the proteins that DNA wraps around. The researchers reasoned that compounds that interfere with histone deacetylation might inhibit cocaine dependence. They showed that histone deacetylase inhibitors such as trichostatin A decreased the tendency of rats to take cocaine.

Modified Calixarene Boosts DNA Delivery

By changing the structure of a macrocyclic compound, researchers in Italy have created a more efficient type of reagent for transfection, which is the delivery of DNA or RNA into cells (Org. Lett., DOI: 10.1021/ol801326d). Genetic engineers use transfection reagents to alter a cell's gene expression and protein production. A team led by Francesco Sansone and Rocco Ungaro of the University of Parma reports preliminary studies showing that a formulation containing a calix[4]arene macrocycle delivers DNA more reliably than a commercially available transfection reagent. The team had previously modified the aromatic rings on calix[4]arenes with guanidinium groups, which are known to ferry compounds into cells. The macrocycles bound DNA, but they were inefficient at transfection and toxic to cells. In the team's new calix[4]arenes, the attachment points for the guanidinium moieties are hydroxyl groups, to good effect. The new reagents have low toxicity and efficiently transport DNA into a variety of cells. Traditional viral transfection agents can provoke an immune response, Sansone says. Lipid-based agents don't work in every type of cell, and most are poorly structurally characterized, impeding mechanistic studies aimed at improving them, he adds. The team now hopes to exploit calixarenes' synthetic flexibility to carry out such optimization studies.

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